The structure and physical properties of human non-pancreatic secretory phospholipase A2 (hereinafter called, “sPLA2”) has been thoroughly described in two articles, namely, “Cloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluid” by Seilhamer, Jeffrey.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, issue of Apr. 5, pp. 5335–5338, 1989; and “Structure and Properties of a Human Non-pancreatic Phospholipase A2” by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of Apr. 5, pp. 5768–5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds, which inhibit sPLA2 mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in the general treatment of conditions induced and/or maintained by overproduction of sPLA2; such as sepsis, and pain. The treatment of sepsis for example, represents an important unmet medical need for which compounds of the present invention may be used.